This invention relates to 17xcex1-hydroxy-4-androstene-3-one and its derivatives, methods for their production, and pharmaceuticals containing these compounds.
It is known from the state of the art that natural testosterone and follicle-stimulating hormone (FSH) are important regulatory components of spermatogenesis. As the gametes themselves have no FSH receptors, hormonal signals have to be transferred via Sertoli cells that produce unknown signals required for spermatogenesis (de Kretser D. M. et al., Hum. Reprod., 1998, 13, pp. 1-8). The FSH concentration is regulated using inhibin-B (negative feedback) that is released from the Sertoli cells. Inhibin-B itself inhibits the secretion of FSH, thereby suppressing spermatogenesis. This is why inhibin-B is considered to be a marker of spermatogenesis (Pierik F. H. et al., J. Clin. Endocrinol. Metab., 1998, 83, pp. 3110-3114) and why it plays a vital role in the paracrine and endocrine regulation of spermatogenesis as a function of its concentration. A correlation of inhibin-B and sperm concentration has also been reported (Klingmuller D. et al., Hum. Reprod., 1997, 12, pp. 3276-3278; Jensen D. K. et al., J. Clin. Endocrinol. Metab., 1997, 82, pp. 4059-4063).
Epitestosterone, an androgene that is secreted in the testicles, has long been regarded as an inactive epimer of testosterone. It has been found in the past few years, however, that it has either an inhibiting or an increasing effect on FSH levels in the plasma depending on its dose (Bicikova M. et al., J. Steroid. Biochem. Mol. Biol., 1993, 45, pp. 321-324). In this context, epitestosterone is described as a competitive inhibitor of androgen receptors (antiandrogen) (Lapcik O. et al., J. Endocrinol., 1994, 143, pp. 353-358; Starka L. et al., Vnitr. Lek., 1996, 42, pp. 620-623). In addition, it has been described that epitestosterone inhibits epididymal and prostatic 5xcex1-reductase (Monsalve A. and Blaquier J. A., Steroids, 1977, 30, p. 41-51; Starka L. et al., J. Steroid. Biochem., 1989, 33, pp. 1019-1021). Starka et al. discussed an assumed connection between antiandrogenic activity and 5xcex1-reductase inhibition (Starka L. et al., J. Steroid. Biochem., 1989, 33, pp. 1019-1021). Furthermore, it influences the conversion of testosterone into estrogens by aromatization (Broulik P. D. et al., Bone, 1997, 20, pp. 473-475).
It is one of the problems of this invention to provide known and new compounds with high efficacy for contraceptive uses and for hormone replacement therapy in men.
This problem is solved according to the invention by providing 17xcex1-hydroxy-4-androstene-3-one or its derivatives of the general formula I 
wherein
the residues R each independently represent a hydrogen atom or an OR2 residue, where
the R2 residues independently represent hydrogen atoms, saturated or unsaturated, straight-chain or branched alkyl or acyl groups containing 1 to 6 C atoms,
R1 is a saturated or unsaturated, straight-chain or branched acyl group containing 1 to 18 C atoms, a benzoyl, methylbenzoyl, or alkylbenzoyl group containing up to 10 C atoms, a sulfite or a glucuronyl residue, and each Rxe2x80x2 residue represents a hydrogen atom or form a double bond together with the single bond between C11 and C12, and their pharmaceutically tolerable salts.
It is preferred according to the invention that R1 is an undecanoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, acetyl, caproyl, benzoyl, valeroyl, sulfite, or glucuronyl residue.
The compounds according to the invention of the general formula I can be administered either in their free form or as pharmacologically effective salts. Suitable examples of these salts of compounds of the general formula I include addition salts of common physiologically compatible inorganic and organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipinic acid, and benzoic acid. Other acids that can be used are described, for example, in Arzneimittelforschung, vol. 10, pp. 224-225, Birkhxc3xa4user Verlag, Basel and Stuttgart, 1966, and in Journal of Pharmaceutical Sciences, vol. 66, pp. 1-5 (1977).
The addition salts of acids are obtained in a generally known way by intermixing the free base or its solutions with the respective acid or its solutions in an organic solvent such as methanol, ethanol, n-propanol, or isopropanol, or a lower ketone such as acetone, methyl ethyl ketone, or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofurane, or dioxane. Mixtures of the solvents mentioned above can be used to improve crystallization. In addition, physiologically compatible aqueous solutions of acid addition salts of the compound of the general formula I can be produced in an aqueous acidic solution.
The acid addition salts of compounds of the general formula I can be converted into the free base in a generally known way, e. g. using alkalies or ion exchangers. Other salts can be obtained by reacting the free base with inorganic or organic acids, especially such acids that are suited for forming therapeutically applicable salts. These and other salts of the new compound such as picrate can also be used to purify the free base by converting it into a salt, isolating this salt, and releasing the base from it.
The new derivatives of the invention of 17xcex1-hydroxy-4-androstene-3-one are produced by partial synthesis (see Tetrahedron Lett. 35, p. 2329 (1994)). To do this, 14,15-unsaturated 17xcex1-hydroxy-4-androstene-3-one is reacted with methyl dihalides and a zinc-copper pair or diazomethane and zinc iodide to the respective 14xcex1, 15xcex1-methylene-17xcex1-ols. The derivatives of the invention that contain a 14,15-methylene group are synthesized with knowledge of the chemical reactions described in German patent no. DE 42 39 946. Alternatively, you the following method can be applied: To maintain an existing 17-oxo grouping, transform the derivative into ethylene ketal. The following steps are adding bromine to produce the respective 16xcex1 bromine compound and transformation into the xcex9415 compound in a hydrobromination step. After isomerization to produce the xcex9414 compound and splitting up said compound, the existing 17-oxosteroids are reduced with complex metal hydrides or diborane in a tetrahydrofurane solution at xe2x88x9210 to +10xc2x0 C. Various substituents can be inserted, for example, at positions 11 or 12, again by partial synthesis. A suitable oxygen function is inserted in the molecule by adding ceric ammonium nitrate (see Terahedron Lett. 35, p. 8599 (1994)).
Another object of this invention are pharmaceutical preparations for oral, parenteral, topical, rectal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intrabuccal or sublingual application which, in addition to the common substrates and diluents, contain as active ingredient at least one compound according to the invention of the general formula I or its acid addition salt.
The pharmaceuticals of the invention are produced in a generally known way using the common solid or liquid substrates or diluents and the commonly used adjuvants of pharmaceutical engineering, their dosage depending on the intended application. Preferred preparations are forms of application suitable for oral administration. Such forms of application include tablets, film tablets, lozenges, capsules, pills, powder, solutions or suspensions, or depot systems.
Parenteral preparations such as injection solutions can also be taken into consideration, of course. Another example of suitable preparations are suppositories.
The respective tablets can be produced, for example, by intermixing the active ingredient with known adjuvants, e. g. inert diluents such as dextrose, sugar, sorbitol, mannite, polyvinylpyrrolidone, blasting agents such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents for producing a depot effect such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also consist of multiple layers.
Accordingly, lozenges can be produced by coating the cores produced in a similar way as the tablets with agents that are typically used in lozenge coatings, e. g. polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide, or sugar. The lozenge coating may consist of multiple layers, and the adjuvants listed above for tablets can be used here as well.
Solutions or suspensions with the active agent of the invention may further contain sweetening agents such as saccharin, cyclamate or sugar as well as aromatizers such as vanillin or orange extract. They may further contain suspending agents such as sodiumcarboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active agent with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.
Suitable suppositories can be produced, for example, by intermixing with the respective substrates such as neutral fats or polyethylene glycol or their derivatives.
Moreover, transdermal systems are an object of this invention. Such systems are sticking plaster, patches or topical forms of application as well as injectable implants. The manufacturing of such systems is known to the expert skilled in the art.
The advantages of this invention result from the fact that new pharmaceutical preparations for regulating spermatogenesis and for hormone replacement therapy are provided which contain active ingredients that have a novel profile of efficacy and/or a high efficacy as regards stimulation of inhibin-B.